This Mentored Clinical Scientist Development Award is designed to support the development a of dedicated investigator of the pathogenic mechanisms of systemic autoimmune diseases. The Principal Investigator (PI) has developed expertise in the investigation of the regulation of T helper cell function and has applied his training to studies of T cell regulation in SLE, the prototype systemic autoimmune disease. The career development plan will be supervised by a sponsor, Dr. Crow, and a co-sponsor, Dr. Ivashkiv, who provide complementary expertise in the areas of T cell regulation and analysis of intracellular signaling pathways. The PI will benefit from the focused basic research and clinical activities at Hospital for Special Surgery, known for its contributions to the characterization of pathogenic mechanisms of rheumatic diseases. In addition, he will draw on the rich scientific and educational resources of Weill Graduate School of Medical Sciences and its medical school for supplemental coursework in molecular biology and immunology, seminars, and scientific collaboration. The goal of the PI is to achieve scientific independence in the area of regulation of the immune response as a basic investigator in an academic rheumatology program. The research project will explore the role of mRNA stability in the regulation of CD40L, a key mediator of T cell help to B cells that has been implicated in SLE pathogenesis. The hypothesis to be investigated is that PKA and CaMKIV act in synergy to stabilize CD40L mRNA by activating a specific CD40L 3'UTR mRNA-binding protein (RBP). It is suggested that a primary or secondary alteration of the availability of cytoplasmic CD40L-specific RBP accounts for the altered mRNA stability observed in SLE T cells. To investigate this hypothesis we will: 1) study the role of the cAMP-PKA and Ca2+-CaMKIV pathways in T cell CD40L mRNA stability, and 2) study the regulation of CD40L mRNA stability in SLE T cells. The research project will provide a scientific focus for continued development of the Pl's expertise in the study of intracellular signaling pathways, allow the development of an independent research program, and provide new insights into the mechanisms of normal and altered T cell regulation that will have important implications for modulation of the autoimmune response.